HIV CNS disease is consistently associated with infiltration and activation of macrophages/microglia, enhanced production of proinflammatory cytokines, increased expression of proapoptotic and neurotoxic mediators, and neuronal loss. A number of neuroprotective therapeutics are being examined, but no single agent has emerged as the solution to the inflammatory and neurodegenerative effects of HIV in the CNS. The recent identification of the tetracycline derivative, minocycline, as a potent anti-inflammatory and neuroprotective drug that also inhibits HIV replication in macrophages, microglial cells, and astrocytes demands the examination of this readily available generic drug as a neuroprotective agent in HIV infection. We have developed an accelerated, consistent SIV/macaque model (SIV-AC) of HIV CNS disease in which over 90% of infected animals develop encephalitis with neurodegeneration as evidenced by increased expression of B-APP and B-amyloid and evidence of neuronal degeneration/apoptosis in the CSF and brain. This model recapitulates the acute, asymptomatic, and terminal characteristics of HIV infection in humans on a highly reproducible time schedule. Our recent studies using this model have demonstrated that the development of SIV encephalitis coincides with an imbalance between the antiapoptotic ERK signaling pathways and the proapoptotic JNK and p38 signaling pathways, representing a failure to maintain a homeostatic balance in the CNS. Our hypothesis is that minocycline will play a dual neuroprotective role in SIV-infected macaques: a) by inhibiting pathologic activation of p38 thus reestablishing a balance between pro-and antiapoptotic pathways, and b) by inhibiting SIV replication and hence the production of viral neurotoxic proteins in the CNS. This application proposes integrated in vivo and in vitro studies to examine the mechanisms by which minocycline exerts its palliative effects on the CNS. In Aim 1 we propose to measure the effects of minocycline on virus replication and on the development of CNS inflammatory and neurodegenerative changes in SIV-infected macaques. In Aims 2 and 3 we will identify the mechanism(s) by which minocycline protects against neurotoxicity and suppresses SIV/HIV replication in macrophages, microglia and astrocytes. Theses mechanistic studies are important given the potential of minocycline to act not only as a neuroprotective agent but also as a viral suppressive agent in the CNS. [unreadable] [unreadable]